: This project is focused on studies of the mechanism of transplantation tolerance induced by mixed allogeneic and syngeneic bone marrow transplantation in a murine model. The major goal is to examine the influence of various genetic barriers on the induction of mixed chimerism and to determine the mechanism of tolerance induction. Experiments are designed to evaluate the role of T cell subsets and NK cells in resisting engraftment across selected MHC and non-MHC barriers, to determine the mechanism whereby tolerance is maintained by persistence of allogeneic lymphohematopoietic elements, to determine the ability of tolerance to withstand challenge with normal non-tolerant recipient strain T cells, to evaluate the susceptibility of chimeras prepared by a non-myeloablative conditioning regimen to the induction of GVHD by administration of donor T cells, and, to evaluate clonal deletion of the specific allo-reactive T cells by in vitro assays of cellular immunity and by detection of recipient T cells bearing donor reactive V-beta by flow cytometry. It is hoped that these studies will provide insight into the mechanisms of tolerance induced by a new non-lethal preparative regimen as well as into the potential application of this method for induction of specific transplantation tolerance across histocompatibility barriers.